SK287988B6 - Composition, oral dosage form and use thereof - Google Patents

Abstract

Composition comprising 10 wt.-% ezetimibe, 55 wt.-% lactose monohydrate, 20 wt.-% microcrystalline cellulose NF, 4 wt.-% povidone (K29-32) USP, 8 wt.-% croscaramellose sodium NF, 2 wt.-% laurylsulfate sodium and 1 wt.-% magnesium stearate. Disclosed are also oral dosage form comprising the aforementioned composition and use of the composition for the manufacture of a medicament for co-administration with a PPAR activator to treat and/or prevent the vascular conditions comprising arteriosclerosis, hypercholesterolemia, sitosterolemia, stroke, diabetes, obesity and lowering of plasma levels of cholesterol and/or sterol in mammals.

Description

Technical field

The invention relates to compositions comprising peroxisome proliferator-activated receptor (s) (PPAR) activator (s) and some sterol absorption inhibitor (s) for the treatment of disease vascular and lipidic conditions, such as those associated with atherosclerosis, hypercholesterolemia and other vascular disease. conditions in mammals.

This application is based on U.S. Provisional Patent Application Ser. No. 60/264396 filed Jan. 26, 2001 and U.S. Provisional Patent Application Ser. 60 / 323,839, filed Sep. 21, 2001, which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Atherosclerotic coronary heart disease (CHD) is the leading cause of death and vascular morbidity in the Western world. Risk factors for atherosclerotic coronary heart disease include high blood pressure, diabetes melitus, family history, male gender, cigarette smoke, and serum cholesterol. Total cholesterol levels greater than 225 to 250 mg / dl are associated with a marked increase in the risk of CHD.

Cholesteryl esters are a major component of atherosclerotic lesions and a major form of cholesterol deposition in arterial wall cells. The formation of cholesteryl esters is also a step in the absorption of cholesterol from food in the intestine. Thus, inhibiting cholesteryl ester formation and lowering serum cholesterol may inhibit the progression of atherosclerotic lesions, reduce cholesteryl ester accumulation in the arterial wall, and block the absorption of cholesterol from food in the intestine.

Regulation of total body cholesterol homeostasis in mammals and animals includes regulation of dietary cholesterol intake and modulation of cholesterol biosynthesis, bile acid biosynthesis and catabolism of cholesterol-containing plasma lipoproteins. The liver is the major organ responsible for cholesterol biosynthesis and catabolism and is therefore the primary determinant of plasma cholesterol levels. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL), which are subsequently metabolized to low density lipoproteins (LDL) in the bloodstream. LDLs are the predominant cholesterol-bearing lipoproteins in plasma and the increase in their concentration is correlated with increased atherosclerosis. When the intestinal cholesterol absorption is reduced by any means, less cholesterol is delivered to the liver. The effect of this action is a decreased production of hepatic lipoprotein (VLDL) and an increase in hepatic clearance of plasma cholesterol, mostly LDL. Thus, the net effect of inhibiting intestinal cholesterol absorption is a decrease in plasma cholesterol levels.

2-Methyl-2-phenoxypropionic acid (fibric acid) derivatives, such as fenofibrate, gemfibrozil and clofibrate, have already been used to lower triglyceride levels, slightly lower LDL levels and increase HDL levels. 2-Methyl-2-phenoxypropionic acid derivatives are also known as activators of peroxisome proliferator-activated alpha receptor.

U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787 disclose hydroxy-substituted azetidinone compounds and substituted β-lactam compounds useful for lowering cholesterol levels and / or inhibiting the formation of cholesterol-containing lesions in the walls of mammalian arteries. U.S. Pat. Nos. 5,846,966 and 5,661,145 disclose hydroxy-substituted azetidinone compounds or substituted β-lactam compounds in conjunction with HMG-CoA reductase inhibitors for preventing or treating atherosclerosis and lowering plasma cholesterol levels.

PCT patent application no. WO 00/38725 discloses cardiovascular therapeutic combinations comprising an inhibitor of intestinal bile acid transport or a protein inhibitor of cholesteryl ester transport in conjunction with a 2-methyl-2-phenoxypropionic acid derivative, a nicotinic acid derivative, a protein inhibitor of microsomal triglyceride transfer, with an antagonist substance sterol, phytosterol, stanol, an antihypertensive agent or a bile acid sequestrant.

U.S. Pat. No. 5,698,527 discloses disaccharide-substituted ergostanone derivatives as cholesterol absorption inhibitors used alone or in conjunction with certain other cholesterol lowering agents useful for the treatment of hypercholesterolemia and related disorders.

Notwithstanding recent improvements in the treatment of vascular diseases, there remains a need in the art for improved means and for the treatment of hyperlipidemia, atherosclerosis and other vascular conditions.

SUMMARY OF THE INVENTION

The present invention provides a composition comprising:

(a) 10 wt. the active compound of formula (1);

(b) 55 wt. lactose monohydrate;

(c) 20 wt. microcrystalline cellulose N F;

(d) 4 wt. povidone (K29-32) USP;

(e) 8 wt. croscarmellose sodium NF;

(f) 2 wt. sodium lauryl sulfate; and (g) 1 wt. magnesium stearate;

wherein the term active compound of formula (I) denotes

The invention also provides pharmaceutical compositions for treating or preventing vascular disease states, diabetes, obesity, or reducing the concentration of sterols in a mammalian plasma comprising a therapeutically effective amount of said composition and a pharmaceutically acceptable carrier.

All numbers other than those in the operating examples or, unless otherwise indicated, expressing the amounts of the components, reaction conditions and the like, hereinafter used in the description of the invention and the claims, shall be understood to be modified in all cases by "about".

The compositions of the invention are set forth in the claims.

The term "therapeutically effective amount" means that amount of the therapeutic agent in the compositions, for example, an activator of a peroxisome proliferator-activated receptor (s), a sterol absorption inhibitor (s), and another pharmacological or therapeutic agent described later that elicits a biological or medical response. or a mammal contemplated by the administering person (such as a researcher, physician or veterinarian), which includes alleviating the symptoms of the disease state or disease being treated and preventing, slowing or arresting the progression of one or more conditions, such as vascular conditions such as hyperlipidemia (e.g. atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and / or lowering of plasma sterol (s) (such as cholesterol).

The terms "combination therapy" or "therapeutic combination" are used herein to mean administering two or more therapeutic agents, such as an activator of a peroxisome proliferator-activated receptor (s) and a sterol absorption inhibitor (s), to prevent or treat a disease condition. conditions such as vascular disease states such as hyperlipidemia (e.g. atherosclerosis, hypercholesterolemia or sitosterolemia), vascular inflammation, stroke, diabetes, obesity and / or lowering of plasma sterol (s) (such as cholesterol). As used herein, the term "vascular" includes cardiovascular, cerebrovascular and combinations thereof. The compositions of the invention may be administered by any suitable means that cause the compounds to contact the site of action in the body, for example, in a plasma, liver, or small intestine of a mammal or human. Such administration involves co-administering these therapeutic agents in a substantially simultaneous manner, such as in a single tablet or capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each therapeutic agent. Such administration also involves the use of each type of therapeutic agent in a sequential manner. In any case, however, treatment using the combination therapy will provide a beneficial effect in the treatment of the disease state. A potential advantage of the combination therapy described herein may be to reduce the required amount of individual therapeutic agents or the total cumulative amount of therapeutic compounds that are effective in treating a disease state. By using a combination of therapeutic agents, the side effects of the individual agents can be reduced compared to monotherapy, which can improve patient compliance. The therapeutic agents may also be selected to provide a broader range of complementary effects or complementary modes of action.

The sterol inhibitor in the compositions of the invention has the formula (II) (ezetimibe) shown below:

or a pharmaceutically acceptable salt or solvate of a compound of formula (II).

Compounds of formula (II) may be prepared by a variety of methods well known to those skilled in the art, such as described in US Pat. 5,631,365, 5,767,115, 5,846,966, 6,207,822, U.S. provisional patent application no. 60 / 279,288 filed March 28, 2001 and PCT patent application WO 93/02048, and in the example given later.

The daily dose of the sterol absorption inhibitor (s) may range from about 0.1 to about 1000 mg per day, preferably about 0.25 to about 50 mg / day, and more preferably about 10 mg per day, given in a single dose or 2 to 2 mg. 4 divided doses. The exact dose, however, is determined by the attending physician and is dependent upon the potency of the compound administered, the age, weight, condition and response of the patient.

When administering pharmaceutically acceptable salts of said compounds, the weights indicated above refer to the weight of acid equivalent or base equivalent of the therapeutic compounds obtained from the salt.

The compositions of the invention may be administered to a mammal in need of such treatment in a therapeutically effective amount to treat one or more disease states, for example, vascular diseases such as atherosclerosis, hyperlipidemia (including but not limited to hypercholesterolemia, hypertriglyceridemia, sitosterolemia ), vascular inflammation, stroke, diabetes, obesity and / or lowering of plasma sterol (s). The compositions may be administered by any suitable method that makes contact of these compounds with the site of action in the body, for example, in a plasma, liver, or small intestine of a mammal or human.

The daily dose of the various compositions described above may be administered to the patient in a single dose or in multiple subdoses, as desired. Subdoses may be administered, for example, 2 to 6 times per day. Sustained-release doses may be used. When the peroxisome proliferator-activated receptor activator (s) and sterol absorption inhibitor (s) are administered in separate doses, the number of doses for each component given per day may not necessarily be the same, for example one component may have a longer duration of activity and less frequently.

Pharmaceutical compositions for treatment of the invention may further comprise one or more pharmaceutically acceptable carriers, one or more excipients and / or one or more additives. Examples of pharmaceutically acceptable carriers include solids and / or liquids such as ethanol, glycerol, water and the like. The amount of carrier in the medicament composition may range from about 5 to about 99% by weight of the total weight of the medicament or therapeutic combination. Examples of suitable pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders such as starch, disintegrants, buffers, preservatives, antioxidants, lubricants, flavors, thickeners, coloring agents, emulsifiers and the like. The amount of excipient or additive may range from about 0.1 to about 90 weight percent of the total weight of the drug composition or therapeutic combination. The person skilled in the art understands that the amount of carrier (s), excipients and additives (if present) may vary.

The pharmaceutical compositions of the invention may be administered in any conventional dosage form, preferably in an oral dosage form, such as capsules, tablets, powder, wafers, suspensions or solutions. Compositions and pharmaceutical compositions can be prepared using conventional pharmaceutically acceptable and conventional techniques. Several examples of preparation of dosage formulations are given later.

The following compositions exemplify some of the dosage forms of the invention. In all mixtures, the term "active compound I" refers to a compound of formula (II) described hereinbefore, or isomers of a compound of formula (II), or pharmaceutically acceptable salts or solvates of a compound of formula (II).

Example

tablets

no. 1 component Active compound I mg / tablet 10 2 Lactose monohydrate N F 55 3 Microcrystalline cellulose NF 20 4 Polyvinylpyrrolidone (K29-32) USP 4 5 Carboxymethylcellulose sodium NF 8 6 Sodium lauryl sulfate 2 7 Magnesium stearate NF 1 Pretty 100

The tablets described herein may be co-administered with tablets, capsules, etc. that include a dose of PPAR activator, for example, TRICOR® capsules as described.

Method of production

In a suitable blender, mix item no. 4 with purified water to form a binder solution. Items 1, 2, 6 and part of item 5 are sprayed with a binder solution and then water in a fluidized bed apparatus, thereby granulating the components. Fluidization is continued to dry the wet granules. The dried granules are sieved and mixed with item no. 3 and the remaining item no. 5. Item No 1 is added. 7 and mixed. The mixture is compressed to a suitable size and weight using a suitable tabletting machine.

For co-administration in separate tablets or capsules, representative compositions that include a cholesterol absorption inhibitor, such as discussed above, are well known in the art, and representative compositions that include a peroxisome proliferator-activated receptor activator, such as e.g. are, for example, discussed earlier. It is contemplated that when the two active ingredients are administered as a single composition, the dosage forms described for the compounds of formula (II) can be readily modified using the knowledge of one skilled in the art.

Since the present invention relates to the treatment of conditions such as discussed earlier, such as to reduce plasma sterol (or particularly cholesterol) concentrations or levels by treating a combination of active ingredients where the active ingredients can be administered separately, the invention also relates to combining separate pharmaceutical compositions in the form of kit. That is, a kit is contemplated where there is a combination of two separate units: a pharmaceutical composition comprising at least one activator of a peroxisome proliferator-activated receptor and a separate pharmaceutical composition comprising at least one sterol absorption inhibitor as described. The kit will preferably include instructions for administering the separate components. The kit form is particularly advantageous when the separate components have to be administered in different dosage forms (e.g. oral and parenteral) or are administered at different dosage intervals.

The medicaments of the invention may inhibit intestinal cholesterol absorption in mammals as exemplified later and may be useful for the treatment and / or prevention of disease states, for example vascular diseases such as atherosclerosis, hypercholesterolemia and sitosterolemia, stroke, obesity and to reduce plasma cholesterol levels in mammals, particularly humans.

In another embodiment of the invention, the compositions of the invention may inhibit sterol absorption or decrease the plasma concentration of at least one sterol selected from the group consisting of: phytosterols (such as sitosterol, campesterol, stigmasterol, and avenosterol), 5α-stanols (such as cholestanol, 5a-campestanol, 5a-sitostanol), cholesterol and mixtures thereof. The plasma concentration may be reduced by administering to a mammal in need of such treatment an effective amount of at least one medicament comprising at least one PPAR activator and at least one sterol absorption inhibitor of formula (II) described above. The reduction in plasma sterol concentration may range from about 1 to about 70 percent, and preferably about 10 to about 50 percent. Methods for measuring total serum cholesterol and total LDL cholesterol are well known to those skilled in the art and include, for example, those described in PCT WO 99/38498 on page 11. Methods for determining the level of other serum sterols are described in H. Gylling et al. ., "Serol Sterols During Stanol Ester Feeding in a Mildly Hypercholesterolemic Population", J. Lipid Res. 40: 593-600 (1999).

The following examples are not part of the invention, but are important for understanding the invention. Unless otherwise indicated, all parts and percentages in the following examples as well as in the claims are by weight.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of the compound of formula (II)

Step 1): To a solution of (S) -4-phenyl-2-oxazolidinone (41 g, 0.25 mol) in CH ₂ Cl ₂ (200 mL) was added 4-dimethylaminopyridine (2.5 g, 0.02 mol) ) and triethylamine (84.7 mL, 0.61 mol) and the reaction mixture was cooled to 0 ° C. Methyl 4- (chloroformyl) butyrate (50 g, 0.3 mol) was added dropwise in CH ₂ Cl ₂ (375 mL) over 1 hour, and the reaction mixture was allowed to warm to 22 ° C. After 17 hours, water and H ₂ SO ₄ (1M, 100 mL) were added and the layers were separated and the organic layer was washed sequentially with NaOH (10%), NaCl (saturated) and water. The organic layer was dried over MgSO ₄ and concentrated to give a semi-crystalline product.

Step 2): To a solution of TiCl ₄ (18.2 mL, 0.165 mol) in CH ₂ Cl ₂ (600 mL) at 0 ° C was added titanium isopropoxide (16.5 mL, 0.055 mol). After 15 minutes, the product of Step 1 (49.0 g, 0.17 mol) was added as a solution in CH ₂ Cl ₂ (100 mL). After 5 minutes, diisopropylethylamine (DIPEA) (65.2 mL, 0.37 mol) was added and the reaction mixture was stirred at 0 ° C for 1 hour. The reaction mixture was cooled to -20 ° C, 4-benzyloxybenzylidine (4-fluoro) aniline (114.3 g, 0.37 mol) was added as a solid. The reaction mixture was vigorously stirred for 4 hours at -20 ° C. Acetic acid was then added dropwise in CH ₂ Cl ₂ over 15 minutes, the reaction mixture was allowed to warm to 0 ° C and H ₂ SO ₄ (1 mol / L) was added. The reaction mixture was stirred for an additional 1 hour, the layers were separated, washed with water, separated and the organic layer was dried. The crude product was crystallized from ethanol / water to give the pure intermediate.

Step 3): To a solution of the product of Step 2 (8.9 g, 14.9 mmol) in toluene (100 mL) at 50 ° C was added N, O-bis (trimethylsilyl) acetamide (BSA) (7.50 mL). , 30.3 mmol). After 0.5 h, solid TBAF (0.39 g, 1.5 mmol) was added and the reaction mixture was stirred at 50 ° C for an additional 3 h. The reaction mixture was cooled to 22 ° C, CH ₃ OH (10 mL) was added. The reaction mixture was washed with HCl (1M), NaHCO ₃ (1M) and NaCl (saturated), and the organic layer was dried over MgSO ₄ .

Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH ₃ OH (3 mL) was added water (1 mL) and LiOH.H ₂ O (102 mg, 2.4 mmol) ). The reaction mixture was stirred at 22 ° C for 1 hour and then additional LiOH.H ₂ O (54 mg, 1.3 mmol) was added. After a total of 2 hours, HCl (1M) and EtOAc were added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resulting product (0.91 g, 2.2 mmol) in CH ₂ Cl ₂ at 22 ° C was added C1COCOCl (0.29 mL, 3.3 mmol) and the mixture was stirred for 16 hours. The solvent was removed in vacuo.

Step 5): To a vigorously stirred suspension of 4-fluorophenylzinc chloride (4.4 mmol) prepared from 4-fluorophenylmagnesium bromide (1 mol / L in THF, 4.4 mL, 4.4 mmol) and ZnCl ₂ (0.6 g, Tetrakis (triphenylphosphine) palladium (0.25 g, 0.21 mmol) was added at 4 ° C, followed by the product of step 4 (0.94 g, 2.2 mmol) as a solution in THF (2 mL). The reaction mixture was stirred for 1 hour at 0 ° C and then for 0.5 hour at 22 ° C. HCl (1M, 5 mL) was added and the mixture was extracted with EtOAc. The organic layer was concentrated to an oil and purified by silica gel chromatography to give 1- (4-fluorophenyl) -4 (S) - (4-hydroxyphenyl) -3 (R) - (3-oxo-3-phenylpropyl) -2-azetidinone:

HRMS calcd for C ₂₄ H ₁₉ F ₂ NO ₃ = 408.1429, found 408.1411.

Step 6): To the product of Step 5 (0.95 g, 1.91 mmol) in THF (3 mL) was added (R) -tetrahydro-1-methyl-3,3-diphenyl-1 H, 3 H). -pyrrolo- [1,2-c] [1,3,2] oxazaborol (120 mg, 0.43 mmol) and the mixture was cooled to -20 ° C. After 5 min, borohydride-dimethylsulfide complex (2 mol / L in THF, 0.85 mL, 1.7 mmol) was added dropwise over 0.5 h. After a total of 1.5 hours, CH ₃ OH was added followed by HCl (1M) and the reaction mixture was extracted with EtOAc to give 1- (4-fluorophenyl) -3 (R) - [3 (S) - ( 4-fluorophenyl) -3-hydroxypropyl) -4- (5) - [4- (phenylmethoxy) phenyl] -2-azetidinone (compound 6A-1) as an oil. 1 H in CDCl ₃ □H 3 = 4.68. J = 2.3 Hz. CI (M + H) 500.

Use of (S) -tetrahydro-1-methyl-3,3-diphenyl-17 H, 3 H -pyrrolo [1,2- c] [1,3,2] oxazaborol afforded the corresponding 3 (R) -hydroxypropyl azetidinone (compound 6B-1). H in CDC1 ₃ □ H3 = 4.69. J = 2.3 Hz. CI (M + H) 500.

To a solution of 6A-1 (0.4 g, 0.8 mmol) in ethanol (2 mL) was added 10% Pd / C (0.03 g) and the reaction mixture was stirred at 50 psi (413.7 kPa). 60 psi) of H ₂ gas for 16 hours. The reaction mixture was filtered and the solvent was concentrated to give compound 6A. Mp 164-166 ° C; CI (M + H) 410, [α] D = + 28.1 ° (c ₃ , CH ₃ OH). Elemental analysis for C ₂₄ H ₂₁ F ₂ NO _3: C, 70.41; H, 5.17; N, 3.42; Found C, 70.25; H, 5.19; N, 3.54.

Similar treatment of compound 6B-1 provides compound 6B.

T. t. 129.5-132.5 ° C; CI (M + H) 410. Elemental analysis calculated for C ₂₄ H ₂ [F ₂ NO ₃ : C 70.41; H, 5.17; N, 3.42; Found: C, 70.30; H, 5.14; N, 3.52.

Step 6 '(Alternative): To a solution of the product of Step 5 (0.14 g, 0.3 mmol) in ethanol (2 mL) was added 10% Pd / C (0.03 g) and the reaction mixture was stirred under pressure. 60 psi of H ₂ gas for 16 hours. The reaction mixture was filtered and the solvent was concentrated to give a 1: 1 mixture of 6A and 6B.

In vivo evaluation

In a randomized, placebo-controlled, parallel group trial of 32 healthy hypercholesterolemic people (screening LDL-C> 130 mg / dl) stabilized and maintained on a NCEP Step I diet, they were randomly selected for one of the following four treatments:

Treatment A - placebo given orally as 1 dose per day,

Treatment B - 10 mg of Compound II administered orally as 1 dose per day,

Treatment C - 200 mg L1PANTHYL®, micronized fenofibrate (available from Labortoire Fournier from France) administered orally as 1 dose per day, or

Treatment D - 200 mg LIPANTHYL ® micronized fenofibrate and 10 mg of the compound of formula (II) administered orally as 1 dose per day each morning for 14 days.

Serum lipids were evaluated before dosing (after a minimum of 10 hours without food) on day 1 (baseline), day 7 and day 14.

Results: Mean value (S.E.) at day 14 in percent (%) of change from baseline serum lipid (n = 8) are shown in Table 1:

Table 1

Treatment LDL-C Total-C HDL-C TG A -10.1 (4.9) -8.38 (4.0) -14.1 (2.2) 19.1 (13.9) B -22.3 (5.7) -19.6 (4.0) -13.3 (4.4) -4.57 (12.8) C -13.5 (3.1) -13.0 (2.4) -6.1 (3.6) 0.28 (11.4) D -36.3 (3.5) -27.8 (1.7) -1.97 (4.7) -32.4 (4.5)

Co-administration of 10 mg of the compound of formula (II) and 200 mg fenofibrate (Treatment D) was well tolerated and caused a significant (p <0.03) reduction in LDL-C compared to both the drug and placebo. In this non-patient study where physical activity of subjects was prohibited, HDL-C concentrations tend to decrease and triglycerides tend to increase. The treatment group had the lowest decrease in HDL-C and the highest decrease in triglyceride levels.

Claims (5)

PATENT CLAIMS 1. A composition comprising: (a) 10 wt. the active compound of formula (I); (b) 55 wt. lactose monohydrate; (c) 20 wt. microcrystalline cellulose NF; (d) 4 wt. povidone (K29-32) USP; (e) 8 wt. croscarmellose sodium NF; (f) 2 wt. sodium lauryl sulfate; and (g) 1 wt. magnesium stearate; wherein the term active compound of formula (I) denotes OH F An oral dosage form comprising the composition of claim 1. Oral dosage form according to claim 2, characterized in that it is in the form of a capsule, tablet, powder, lozenge, suspension or solution. Use of a composition according to claim 1 for the manufacture of a medicament for administration together with a PPAR activator for the treatment and / or prevention of vascular conditions including arteriosclerosis, hypercholesterolemia, sitosterolemia, 5 stroke, diabetes, obesity and lowering of plasma cholesterol and / or sterol levels in mammals. End of document